Avelumab is a human monoclonal antibody to programmed cell death receptor ligand 1 (PD-L1), which modulates T cell immune reactivity and is used in the immunotherapy of cancer. Avelumab has major side effects and particularly immune related conditions, including acute liver injury which can be serious and even life threatening.
Avelumab (av el' ue mab) is a human recombinant monoclonal IgG1 antibody to the programmed cell death receptor ligand-1 (PD-L1) which has distinctive immunomodulatory activity and is used in cancer immunotherapy. PD-1 is an important checkpoint molecule that modulates and down regulates T cell responses. Antibody binding to the ligand prevents its binding to the programmed cell death receptor which thereby allows for a continued activation and proliferation of T cells. The subsequent enhancement of cytotoxic reactivity may play a beneficial role in cancer immunotherapy by breaking immunological tolerance to cancer cell neo-antigens. In several multicenter studies, avelumab therapy resulted in objective responses in patients with advanced, metastatic or unresectable malignant neoplasms, and a proportion of patients had a long term remission. Avelumab was approved for use in metastatic Merkel cell carcinoma and advanced, refractory urothelial bladder carcinoma in the United States in 2017, and is currently under evaluation in several other forms of cancer, including NSCLC. Avelumab is available in single use 10 mL vials of 200 mg (20 mg/mL) under the brand name Bavencio. The recommended dose is 2 mg/kg as an intravenous infusion every 2 weeks. Premedication with acetaminophen and antihistamines is recommended for the first 4 infusions. Side effects are common and include fatigue, nausea, musculoskeletal pain, rash and infusion reactions. Between 5% and 20% of treated patients develop immune related side effects as a result of immune enhancement including enterocolitis, dermatitis, endocrinopathy, pneumonitis, neuropathy, nephritis and hepatitis. Most of these reactions respond to dose interruption and/or immunosuppressive therapy, but some have resulted in fatalities and some have required long term therapy. Early recognition and prompt management of these side effects is an integral component of proper use of checkpoint inhibitors such as avelumab.
Mild-to-moderate serum aminotransferase elevations are not common (~1% to 4%) during avelumab therapy, but are usually self-limited and resolve even with continuing cyclic therapy. Serum ALT elevations above 5 times the upper limit of normal (ULN) occur in 0.5% to 1.5% of patients, and a proportion of these individuals develop clinically apparent liver injury that can be severe. The onset of such injury is usually after 2 to 6 cycles or 1 to 3 months after initiation of treatment. The pattern of enzyme elevation is usually hepatocellular. Monitoring of serum enzymes is recommended with dose interruption for values above 3 times the ULN and discontinuation for values above 5 times the ULN. When serum aminotransferase levels remain elevated despite discontinuation or with development of symptoms or jaundice, early intervention with immunosuppressive therapy is prudent and generally results in rapid resolution. Liver histology demonstrates an acute hepatitis-like pattern with focal or confluent necrosis and prominent lymphocytic infiltrates of activated T cells, which is compatible with an immune mediated hepatic injury. Autoantibodies are usually not present and immunoglobulin levels may not be elevated. Restarting avelumab can result in recurrence of injury, although corticosteroid treatment may block recurrence. Immune mediated hepatitis appears to be more frequent with anti-CTLA-4 than with anti-PD1 or anti-PD-L1 checkpoint inhibitors.
The effects of PD-L1 inhibition on chronic hepatitis B have not been reported as enrollment criteria in the clinical trials of avelumab, which have usually excluded patients with chronic viral hepatitis. However, it is likely that anti-PD-L1 treatment would exacerbate chronic hepatitis B by enhancing T cell cytotoxicity to viral antigens. Interestingly, checkpoint immunotherapy has not been found to be deleterious in patients with chronic hepatitis C and in some cases resulted in a decrease in viral levels.
Likelihood score: E* (although no avelumab related cases of clinically apparent immune mediated hepatitis have been described in the literature, this is a relatively recently approved medication and is likely to be a cause of clinically apparent acute liver injury).
Mechanism of Injury
The mechanism of liver injury due to avelumab is likely to be immunologically mediated and many cases of checkpoint related, immune mediated hepatitis have appeared to respond to corticosteroid or immunosuppressive therapy allowing for continuation or restarting of therapy.
Outcome and Management
Guidelines for management of patients receiving avelumab recommend monitoring of liver tests and interrupting therapy for patients who develop persistent serum aminotransferase elevations above 3 times the ULN and discontinuing treatment for values above 5 times the ULN. Corticosteroid therapy can be considered for patients with persistent ALT elevations or if symptoms or jaundice arise, initiating therapy with high dose intravenous methylprednisolone and switching to oral prednisone after 1 to 2 days, continuing tapering doses for at least 30 days. Most cases of hepatitis due to checkpoint inhibitors resolve with prompt institution of immunosuppressive therapy. The few fatal cases that have been reported during immunotherapy with checkpoint inhibitors occurred in patients who had other severe immune related adverse events (Stevens Johnson syndrome, capillary leak syndrome) or who had a delay in starting corticosteroid therapy. Patients with immune related adverse events due to avelumab can frequently restart therapy once the adverse event has resolved, although concurrent immunosuppressive therapy may be necessary.
REPRESENTATIVE TRADE NAMES
Avelumab – Bavencio®
Product labeling at DailyMed, National Library of Medicine, NIH
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References updated: 20 July 2017
Abbreviations used: CTLA-4, cytotoxic T lymphocyte associated antigen 4; PD-L1, programmed cell death receptor ligand-1; NSCLC, non-small cell lung cancer.
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Heery CR, O'Sullivan-Coyne G, Madan RA, Cordes L, Rajan A, Rauckhorst M, Lamping E, et al. Avelumab for metastatic or locally advanced previously treated solid tumours (JAVELIN Solid Tumor): a phase 1a, multicohort, dose-escalation trial. Lancet Oncol 2017; 18: 587-98. PubMed Citation (Among 53 patients with various refractory solid tumors treated with 1 of 4 doses of avelumab every 2 weeks, common side effects were fatigue, flu-like symptoms and fever, and 3 developed autoimmune disorders, one with ALT elevations above 5 times ULN).
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In brief: Avelumab (Bavencio) for metastatic merkel cell carcinoma. Med Lett Drugs Ther 2017; 59 (1521): e120. PubMed Citation (Concise review of the mechanism of action, efficacy, safety and costs of avelumab shortly after its approval in the US as therapy of metastatic Merkel cell carcinoma).
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